Six subjects were taking a stable dose at least 3 months of an angiotensin-converting enzyme inhibitor, which remained unchanged during the study. Participants were not receiving any other medications known to affect carbohydrate metabolism or insulin secretion. All nondiabetic volunteers had a negative family history of T2DM and a normal oral glucose tolerance test. Each subject gave written, informed, voluntary consent before participation.
After the initial screening, eligible subjects were instructed by a dietician to ingest a weight-maintaining American Diabetes Association diet and were seen weekly for 4 weeks to ensure dietary compliance.
During this period they were encouraged to maintain their dietary intake and physical activity constant. If after the 4-week run-in period participants were considered to be compliant with the diet and if their weight had remained stable, they were admitted to the Clinical Research Center for two baseline metabolic studies, which were carried out at h after a h overnight fast: 1 a g OGTT, and 2 a euglycemic insulin clamp, as described below.
The studies were performed with an interval of 3—7 days. Subjects consumed at least g carbohydrates for 3 days before each study. Because vanadium compounds have been reported to reduce blood pressure 2 , 3 , we performed h ambulatory blood pressure monitoring before and after treatment.
The dose was increased every 2—3 days. At 2 weeks all participants were receiving a total daily dose of mg VOSO 4 , divided in mg doses given with breakfast, lunch, and dinner. Most patients achieved this dose after a week with good tolerance.
Subjects were requested to maintain their usual dietary habits and level of daily activity throughout the study.
Patients were followed weekly during the titration period and every 2 weeks thereafter. On each visit to the Clinical Research Center subjects were questioned about their dietary intake and physical activity pattern, overall well-being, compliance with the medication confirmed by pill count , and side-effects using a standard questionnaire.
Vital signs, physical exam, and home glucose-monitoring results were recorded. Blood was drawn for plasma glucose, fructosamine, and HbA 1c determinations on each visit. The total duration of treatment titration plus stable dose was 6 weeks. At the end of the 6 weeks, the OGTT, insulin clamp, and h ambulatory blood pressure monitoring were repeated. Plasma vanadium levels were determined on the euglycemic insulin clamp days before and after the 6-week treatment period, and 6 weeks after discontinuation of VOSO 4 treatment.
Blood was drawn every 30 min for the next 2 h to measure plasma glucose, insulin, and free fatty acid FFA levels. Euglycemic insulin clamp. After this, a vein of the dorsum of the hand was retrogradely cannulated with a second catheter, and the hand was placed in a thermoregulated box at 65 C for arterialization of the venous blood.
Both iv lines were kept patent with a slow infusion of normal saline. The [3- 3 H]glucose constant infusion rate was of 0. After 80 min, five blood samples were drawn at min intervals 80— min for measurement of plasma glucose, FFA, insulin levels, and plasma glucose radioactivity. Total cholesterol, high density lipoprotein cholesterol, and triglycerides were measured by standardized enzymatic procedures using a Hitachi autoanalyzer Roche Molecular Biochemicals.
Intra- and interassay coefficients of variation were 4. Plasma vanadate concentrations were measured according to the method of Mongol et al. North Vancouver, Canada. A steady state plateau of plasma[ 3- 3 H]glucose specific activity was achieved in all subjects during the last 40 min of the basal and euglycemic insulin clamp periods. During the euglycemic insulin infusion period, endogenous glucose production EGP was computed as the difference between the exogenous glucose infusion rate and the isotopically measured rate of plasma glucose appearance.
Negative numbers for EGP were not observed in any study. The rate of total body insulin-mediated glucose disposal was calculated by adding the residual rate of EGP to the rate of exogenous glucose infusion.
Turnover rates are expressed as milligrams per kg lean body mass LBM. Statistically significant differences between the diabetic and control groups were determined by unpaired t test. Where appropriate, regressions were calculated by least squares linear regression analysis. Food intake and physical activity remained stable during the study. Tolerance to VOSO 4 was good, as evaluated by history, physical exam, and routine laboratories.
Symptoms occurred only during the titration period. This patient also had a history of gastrointestinal intolerance to metformin and acarbose monotherapy. No abnormalities in blood chemistries, complete blood count, or urinalysis were observed in any subject. Three subjects had the lumbar spine and hip bone mineral density measurements repeated before and after treatment with no detectable change. Consistent with its longer half-life, the decline in the HbA 1c lagged behind that of fructosamine, but was significantly reduced after 6 weeks of VOSO 4 treatment 8.
Effect of 6 weeks of treatment with vanadyl sulfate on plasma glucose left panel and plasma insulin right panel concentrations during an OGTT in poorly controlled T2DM patients. Basal EGP before left column and after center column 6 weeks of vanadyl sulfate treatment in poorly controlled T2DM patients and in matched nondiabetic controls right column.
The steady state plasma insulin concentrations were well matched during the insulin clamp studies performed before and after treatment pre- vs. A, Correlation between the rate of basal EGP and the FPG concentration in type 2 diabetic patients data from before and after treatment combined.
B, Correlation between the decrement in the rate of basal EGP and the decrement in the FPG concentration after 6 weeks of vanadyl sulfate treatment. EGP was nearly completely suppressed during the insulin infusion period of the euglycemic insulin clamp before and after VOSO 4 treatment 0.
In the basal state, steady state conditions prevail, and the rate of glucose disappearance Rd is identical to the rate of glucose appearance. During the euglycemic insulin clamp Fig. Blood pressure was unchanged when measured on each out-patient visit by the same investigator K. To obtain more detailed information, we measured blood pressure during 24 h with an ambulatory blood pressure-recording device. When diurnal and nocturnal blood pressures were analyzed separately we also failed to observe any differences before and after treatment.
Over the last decade there has accumulated a large body of data that demonstrates that vanadium compounds improve glucose homeostasis and enhance insulin sensitivity in animal models of diabetes 1 — 4. However, only three studies have examined the effect of vanadium in type 2 diabetic subjects with rather conflicting results 26 , 28 , It should be noted that the effect of vanadium is dose dependent 31 — 33 , 41 , 42 and requires at least 4 weeks for a full response 7 , 16 , 32 , Our results demonstrate, for the first time in subjects with type 2 diabetes, that an important mechanism of action of VOSO 4 is to reduce basal EGP, which primarily reflects glucose produced by the liver Consistent with previous results 28 , 29 , VOSO 4 also improved insulinmediated glucose disposal without any change in body weight.
During the oral glucose tolerance test, plasma insulin levels did not change, confirming results from animal 7 , 14 , 16 , 23 , 43 and human 28 studies that VOSO 4 does not stimulate insulin secretion.
The ability of VOSO 4 to ameliorate hepatic insulin resistance and reduce the rate of basal EGP is in agreement with studies performed in animals 6 , 16 , 17 , but such a response has not previously been reported in type 2 diabetic patients 26 , 28 , A modest improvement in the suppression of EGP during euglycemic hyperinsulinemia has been reported in patients with type 2 diabetes 28 , 29 , but neither of these studies observed a decrease in basal EGP with vanadium treatment. As in the present study EGP was nearly completely suppressed during the insulin clamp performed before VOSO 4 treatment, we were unable to examine whether vanadium enhanced hepatic sensitivity to a physiological increment in the plasma insulin concentration.
The mechanism s by which VOSO 4 reduces hepatic glucose output remains to be determined. Recently, it has been proposed that in the liver vanadate inhibits Src homology 2 domains that contain PTPase activity However, other investigators have failed to see an increase in liver insulin receptor autophosphorylation 6 , 7 despite a glucose-lowering effect of vanadate, which suggests a site of action that is distal to the insulin receptor tyrosine kinase.
Consistent with this later scenario, vanadium has been reported to restore in the liver the activity of key glycolytic 12 , 19 , 24 and gluconeogenic enzymes, such as phosphoenolpyruvate carboxykinase 6 , 19 , 22 and glucosephosphatase 22 , 46 , The effect on glucosephosphatase is of particular interest, because chronic hyperglycemia has been shown to stimulate EGP by up-regulating the glucosephosphatase complex, the final step involved in the release of glucose by the liver Vanadyl sulfate increased insulin-stimulated glucose disposal in patients with T2DM.
This observation is consistent with the results reported by Cohen et al. However, an improvement in insulin sensitivity was not found by other investigators 26 , Our results are in agreement with a number of in vitro and in vivo studies that have demonstrated that vanadium salts improve skeletal muscle glucose disposal 13 , 14 , 18 , 23 , 25 , 50 — 54 while stimulating glucose transport 25 , 51 — 55 and glycogen synthesis 13 , 23 , Although vanadium salts are regarded as PTPase inhibitors capable of enhancing IRTK activity 1 — 4 , vanadyl the intracellular form of vanadium is a relatively weak PTPase inhibitor 2 , and stimulation of glucose uptake in muscle seems dissociated from an effect on insulin receptor autophosphorylation 5.
Stimulation of muscle glucose uptake by vanadium may also involve pathways in addition to those stimulated by insulin 51 , In the present study we chose to administer VOSO 4 , because it has no significant toxicity when given to rats for 1 yr at doses approximately to fold higher than those used in this study 60 , Although more work is needed in humans to assess its long-term clinical safety i.
Despite the higher doses of VOSO 4 used in the present study, the incidence of gastrointestinal side-effects mild diarrhea and abdominal discomfort was lower than that in previous studies 26 , 28 , Low and high blood glucose levels can cause medical complications. Minerals such as chromium and vanadyl sulfate can help promote glucose synthesis.
Blood glucose is a form of sugar that is carried across the bloodstream and used as energy. Every organ and cell in the body needs sugar to function. When blood levels become too low, the condition is known as hypoglycemia. Fatigue, irritation, blurred vision, and irregular heartbeats are symptoms of hypoglycemia. Hypoglycemia is a symptom of diabetes. When blood levels become too high, the condition is known as hyperglycemia.
Hyperglycemia is most common in individuals with diabetes. When blood sugar levels are too high the entire body is affected. Symptoms of high blood sugar are similar to symptoms of low blood sugar with the addition of increased thirst and frequent urination.
If blood sugar levels go too high the individual can go into a state of ketoacidosis. Left unchecked the condition can be deadly. Blood sugar levels will fluctuate depending on the time of day, at rest, and with meals. Blood sugar is expected to rise after meals and fall within a couple of hours as the body processes the sugar.
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